ZA200602077B - Combinations comprising alpha-2-delta ligands and serotonin/noradrenaline re-up-take inhibitors - Google Patents

Description

VNVO 2005/025675 PCT/TB2004./002943

COMBINZATIONS COMPRISING ALDHA-2-DELTA LIGANDS AND SEROTONIN / NORADREN ALINE

RE-UPTZ®KE INHIBITORS

FIELD OF THE INVE-NTION

This invention relates to a synergistic combirnation of an alpha-2-delta ligamnd and 2 dual serotonin-noradrenaline re-uptake inhibitor (D-SNRI) or one or both of a selective serotonin re-uptake inhibitor (SSRI) and a selective n_oradrenaline re-uptake inhibitcor (SNR) for —the treatment of pain. It also relates to a methend for treating pain through t=he use of effe -ctive amounts of synergistic combinations of an a_lpha-2-delta ligand and a DSNARI or one or beoth of a SSRI and SNRL

BACKGROUND TO THE- INVENTION

An alpha-2-delta receptor ligand is any molecule which binds to any sub-typmse of the hurnan calcium channel alpha-2-delta sub-unit. The c- alcium channel alpha-2-delta s-ub-unit cormprises a number of receptor sub-types which haves been described in the literaturwe: e.g. - N. 8. Gee, J. P. Brown, V. U. Dissanayake, J. Offord, R. Thurlow, and G. N. W* godruff,

J-BRiol-Chem 271 (10):5768-76, 1996, (type 1); Gongz, J. Hang, W. Kohler, Z. Li, anmd T-Z. Su,

J. Mdembr.Biol. 184 (1):35-43, 2001, (types 2 and 3); E. Marais, N. Klugbauer, and _F.

Hoofmann, Mol. Pharmacol. 59 (5):1243-1248, 2001. (types 2 and 3); and N. Qin, S.. Yagel, M.

L. - Momplaisir, E. E. Codd, and M. R. D'Andrea. Mo -1.Pharmacol. 62 (3):485-496, 22002, (type 4). They may also be known as GABA analogs.

Alpha-2-delta ligands have been described foor a number of indications. Thee best . kniown alpha-2-delta ligand, gabapentin (Neurontin®), 1-(aminomethyl)-cyclohex ya/lacetic acid, was first described in the patent literature in thee patent family comprising US-4024175.

Tie compound is approved for the treatment of epilespsy and neuropathic pain.

A second alpha-2-delta ligand, pregabalin, (S)-(+)-4- - amino-3-(2- meethylpropyl)butanoic acid, is described in European patent application publicastion number

EP641330 as amn anti-convulsant treatment useful in the treatment of epilepsy zand in

EP0934061 for the treatment of pain.

Further, T-nternational Patent Application Publiczation No. WO0128978, desc-tibes a series of novel bicyclic amino acids, their pharmaceutically acceptable salts, and their prodrugs of formwula:

HE OH gn com BY (OA HN COH ’ s or a (CHyn n (CHy)n (CHn 1 1] m v wherein rm is an integer of from 1 to 4, where theres are stereocentres, each cente=r may be independentlys R or S, preferred compounds being tho: se of Formulae I-IV above in which n is an integer of from 2 to 4.

More recently, International Patent Applicatiomn Publication Number WOO0»2/85839 describes alpha-—2-delta ligands of the following formulaee:

HO, hi HO, A rg NHH, Hog NH,

At=y—forz RI R2 ol rR” R= RI" R2

U 0 any ™ "oq NH, Hog NH, HO, Hea HO, Ri

Sam Som : At R1

R2 R2 R2 R2 ™ vn vi) [1

HN HN HN, HN, oe ost Hoo AT HEAT) ® * (0) es)

Ho, NH, HO, NH, HOY Ata

K i. et - io | Je 7

Al R2 Ri A2

R1 R2 A1 R2 RY’ R2 [ - mee mw ory wey wood vue xviii XIX =e xXx eye) e210) ee 0) on pil] a xv wherein R! and TR’ are each independently selected from H,. straight or branched al kyl of 1-6 carbon atoms, cycloalkyl of from 3-6 carbon atoms, phenyl . and benzyl, subject to the proviso that, except in thne case of a tricyclooctane compound of formula (XVID), R? and IR? are not simultaneously Inydrogen; for use in the treatment of a num®¥ber of indications, incluiding pain, together with ceombinations with: selective serotonin reuptake inhibitors, e.g. fluoxetine, paroxetine, citaleopram and sertraline; mixed serotonin-norasdrenaline reuptake inhibitors, e.g. milnacipran, vermlafaxine and duloxetine; and selective noracrenaline reuptake inhibeitors , e.g. reboxetine.

International Patent application No. PCT/IB03/009765, unpublished at the filiing date of the present inveration, describes compounds of the formula I, below:

Rs R; Rs

NH,

OH (Tp wherein ZR, is hydrogen or (C;-Cg)alkyl optionally =substituted with from oere to five fluorine atoms;

R; is hyclrogen or (C;-Cg)alkyl optionally substitute=d with from one to five fluorine atoms; or

R; and Ro, together with the carbon to which they are attached, form a tloaree to six membered cyclo alkyl ring;

R; is (C1~—Ce)alkyl, (Cs-Ce)cycloalkyl, (Cs-Cs)eycloalkyl-(Cy-Cs)alkyl, phenye/l, phenyl- (C1-Cs)alkyl, pymridyl, pyridyl-(C;-Cs)alkyl, phenyl-N(H)-, o=1 pyridyl-N(H)- , where=in each of the foregoing al kyl moieties can be optionally substitutecd with from one to fiv—e fluorine atoms, preferably with from zero to three fluorine atoms, and wherein said pheny~1 and said pyridyl and the phenyl and pyridyl moieties of said phenyl-C C;-Cs)alkyl and said pyridyl-(C;-

Csalkyl, respecatively, can be optionally substituted with from one to three substituents,

preferably with from zero to two substituents, independently selescted from chloro, fluoro, amino, nitro, cyano, (C—-Cs)alkylamino, (C;-Cs)alky!l optionally s-ubstituted with from one to three fluorine atoms zand (C;-Cs)alkoxy optionally substituted with from one to three fluorine atoms;

R, is hydrogen or (C;-Cg)alkyl optionally substituted with Sfrom one to five fluorine atoms;

Rs is hydrogen or- (C;-Cg)alkyl optionally substituted with —from one to five fluorine atoms; and

Re is hydrogen or &C;-Ce)alkyl; ora pharmaceutically acceptable salts thereof.

Many types of neumuaological disorders originate from disturba—nces in brain circuits that convey signals using certain monoamine neurotransmitters. Monoarnmine neurotransmitters include, for example, serostonin (5-HT), norepinephrine (noradrenalimne), and dopamine. These neurotransmitters travel from the terminal of a neuron across a small gap (i.e., the synaptic cleft) and bind to receptor— molecules on the surface of a second neur-on. This binding elicits intracellular changes that initiate or activate a response or change in -the postsynaptic neuron.

Inactivation occurs primamrily by transport (i.., reuptake) of the neureotransmitter back into the presynaptic neuron.

Selective serotonir reuptake inhibitors (SSRIs) function by irhibiting the reuptake of serotonin by afferent neur-ons. SSRI’s well known in the art include but are not limited to sertraline (Zoloft®), sertra_line metabolite demethylsertraline, fluoxetine (Prozac®), norfluoxetine (fluoxetine edesmethyl metabolite), fluvoxamine (Luvosx®), paroxetine (Seroxat®, Paxil®) and its alternative formulation, Paxil-CR®, citaloporam (Celexa®), citalopram metabolite des=xethylcitalopram, escitalopram (Lexapro® ), d,I-fenfluramine (Pondimin®), femoxetine. , ifoxetine, cyanodothiepin, litoxetine, dapcxetine, nefazodone (Serxone®), cericlamine &and trazodone (Desyrel®).

Selective noradrenaaline (or norepinephrine) uptake inhibitors. (SNRIs) function b y increasing noradrenaline 1-.evels. SNRI’s well known in the art inclucle, but are not limited to,

reboxetine (Edronax®) amd all enantiomers of reboxetine=, ie., (R/R,S/S =R/S,S/R), desipramine (Norpraminu®), maprotiline (Ludiomil®), lof epramine (Gam==nil®), mirtazep-ine (Remeron®), oxaprotiline—, fezolamine, tomoxetine, mians erin (Bolvidon®), buproprion (Wellbutrin®), buproprior metabolite hydroxybuproprion , nomifensine (M\aAerital®) and 5 viloxazine (Vivalan®).

Dual serotonin-nosradrenaline re-uptake inhibitors (DSNRIs), which inhibit the reuptake of both serotonimn and norepinephrine include ve=nlafaxine (Effex=or®), venlafaxiine metabolite O-desmethylv “enlafaxine, clomipramine (Anaf=ranil®), clomipramine metabolTite desmethylclomipramine, duloxetine (Cymbalta®), milnaccipran and imipr—amine (T ofranill® or

Janimine®).

The contents of al_1 patents and publications cited —within the present application axre hereby incorporated by re=ference. as

SUMMARY OF THE INVEENTION

It has now been found that combination therapoy with an alplma-2-delta liganed and either a dual serotonin-noeradrenaline re-uptake inhibitor @DSNRI) or one or both of a seleective serotonin re-uptake inhib:itor (SSRI) and a selective noramdrenaline re-up@ake inhibitor (SSNRI) results in improvement= in the treatment of pain. Furthermore, when adminiastered simultaneously, sequentically or separately, the alpha-2-cJelta ligand and either the DSINARI or one or both of the SSRI sand SNRI may interact in a syneergistic manner - to control pain. This synergy allows a reduction in the dose required of each compound, leacding to a reduct=ion in the side effects and enhancement of the clinical utility of the compounds.

Accordingly, the invention provides, as a first aspect, a combination pr—oduct comprising an alpha-2-clelta ligand and either a duaml serotonin-nor.adrenaline re-umptake inhibitor (DSNRI) or onee or both of a selective serotornin re-uptake in“hibitor (SSRI) and a selective noradrenaline -xe-uptake inhibitor (SNRI), omr pharmaceuticzally acceptable salts thereof, with the proviso ~that the compounds (i)-(xxv) of = WO02/85839 in combination with a

Claims (19)

1. A combination for the treatment of pain comprising a synergistic amount of an alpoha- 2-delta ligand and a duael serotonin-noradrenaline re-uptakse inhibitor (DSNRI) or one or both of a selectiwe serotonin re-uptake inhibitor— (SSRI) and a selec=tive noradrenaline re-uptake -inhibitor (SNRI), or pharmaceutically acceptable salts theree=of.

2. A combination accordin_g to claim 1 or 2, wherein the alp=ha-2-delta ligand is seleacted from gabapentin, presgabalin, [(1R,5R,6S)-6-(Aminormethyl)bicyclo[3.2.0Thep>t-6- yljacetic acid, 3-(1-Arminomethyl-cyclohexylmethyl)-4F-[1,2 ,4]oxadiazol-5-one» C- [1-(1H-Tetrazol-5-ylmet=hyl)-cycloheptyl]-methylamine, (38,48 )-(1-Aminomethyl- 3,4- dimethyl-cyclopentyl)-aecetic acid, (10,30, 500)(3-amino-nethyl-bicyclo[3.2.0]heot-3- yl)-acetic acid, (3S,5R_)-3-Aminomethyl-5-methyl-octancoic acid, (3S,5R)-3-am—ino- 5-methyl-heptanoic acicl, (3S,5R)-3-amino-5-methyl-nonzanoic acid and (3S,5R)- 3-Amino-5-methyl-octarnoic acid, or a pharmaceutically ac -ceptable salt thereof.

3. A combination accordingg to claim 1 or 2, wherein the alph=a-2-delta ligand is gabapentin.

4. A combination accordingg to claim 1 or 2, wherein the alphaa-2-delta ligand is pregabalin.

5. A combination accordingg to any one of claims 1-4 where t-he alpha-2-delta ligand i_s in combination with an SSR], or a pharmaceutically acceptabIle salt thereof.

6. A combination accordingg to any one of claims 1-5 wherein the SSRI is selected frorm sertraline, fluoxetine, flu voxamine, paroxetine, citalopram, d,]-fenfluramine, femoxetine, trazodone, c-ericlamine, ifoxetine, cyanodothieppin and litoxetine, or a pharmaceutically acceptzable salt thereof,

7. A combination according to any one of claims 1-6 where thme SSRI is sertraline.

8. A combination according to any one of claims 1-4 where the alpha-2-delta ligand is in combination wifith an SNRI, or a pharmaceutically acceptable salt thereof.

9 A combination ac=cording to any one of claims 1-4 and 8 where=in the SNRI is selected from reboxetine, SS,S-reboxetine, desipramine, maprotiline, lofe=pramine, mianserin, mirtazepine, oxap-xotiline, fezolamine, tomoxetine and bupropri_on, or a pharmaceutically =acceptable salt thereof.

10. A combination acecording to any one of claims 1-4 and 8-9 wherein the SNRI is selected from maporotiline, desipramine, buproprion, reboxetine= and S,S-reboxetine, or a pharmaceuticall—y acceptable salt thereof.

11. A combination ac=cording to any one of claims 1-4 and 8-10 w~herein the SNRI is S,S- reboxetine, or a pharmaceutically acceptable salt thereof.

12. A combination ac=cording to any one of claims 1-4 where the aslpha-2-delta ligand is in combination with a DSNRI, or a pharmaceutically acceptable sz alt thereof.

13. A combination a-ccording to any one of claims 1-4 and 12 wherein the DSNRI is : selected from venlafaxine, venlafaxine metabolite (O-desmethylvenlafaxine, clomipramine, clomipramine metabolite: desmethylclonipramine, duloxetine, milnacipran, and Simipramine, or a pharmaceutically acceptable= salt thereof.

14. A combination according to any one of claims 1-4 and 12-133 wherein the DSNRI is selected from rmiilnacipran, duloxetine and venlafaxine, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition for the curative, prophylactic cor palliative treatment of pain comprising za therapeutically effective amount of a combination according to any one of claims 1-14. or pharmaceutically acceptable sal-ts thereof and a suitabMe carrier of excipient.

16. Use of a syne-xgistic effective amount of an alpha-2=-delta ligand and a DSNIRI or one orboth of aS SRI and SNRI, or pharmaceutically a_cceptable salts thereof, Zin the manufacture of a medicament for the curative, prophylactic or palliative trasatment of pain.

17. Use accordin_g to claim 16 where the pain is neurogpathic pain.

18. A method for the curative, prophylactic or palliatiwe treatment of pain, par—ticularly neuropathic ain, comprising simultaneous, sequemntial or separate adminisstration of a therapeutically synergistic amount of an alpha-2-d_elta ligand and a DSINR_1 or one or both of a SSFRI and SNRI, or pharmaceutically acceptable salts thereof, to a mammal in need of sam d treatment.

19. The method saccording to claim 18 where the pain is neuropathic pain.